Administrative Supplement Request to R21AG058052-01A1, ?Bioenergetic dysfunction in the aging, injured brain: characterization and intervention with creatine? Abstract A history of traumatic brain injury (TBI) is one of the strongest risk factors for Alzheimer's disease and related dementias (AD/ADRD), and evidence suggests that older age at the time of TBI augments the risk. However, the biological mechanisms linking TBI and AD/ADRD?and how these might interact with aging?remain unknown. Our laboratory studies the effects of older age on the pathophysiology of TBI in animal models. Our parent grant (R21AG058052-01A1) aims to i) establish the effects of older age on the brain's bioenergetic response to TBI, and ii) manipulate this response with a dietary creatine treatment, comparing therapeutic efficacy across age and sex. While previous studies have shown that TBI can rapidly induce changes in brain amyloid beta (A?) and tau proteostasis, little is known about how older age at the time of injury may affect the development of A? and tau pathology. To address this knowledge gap, we propose a direct extension of our parent grant that will examine post-TBI changes in brain A? and tau proteostasis as a function of age. Since not all TBI survivors develop aging-related dementia, biomarkers of post-TBI AD risk are needed. Recent evidence has linked elevated circulating cell-free mitochondrial DNA (mtDNA) to TBI severity and patient outcomes, and also to mechanisms of AD/ADRD pathogenesis. We will assess post-TBI changes in blood and CSF cell-free mtDNA as a function of age, and our exploratory study will investigate the possibility that mtDNA constitutes a novel biomarker of post-TBI risk of AD. The proposed studies represent a natural extension of our ongoing research on the bioenergetic response to TBI in the aging brain. Work performed under this supplement will add new knowledge to the still-nascent field of research on the link between TBI and AD/ADRD. The proposed experiments will generate a strong body of preliminary data to support a planned R01 application on mtDNA as a possible link between TBI, aging, and mechanisms of AD/ADRD pathogenesis. These studies are therefore directly responsive to NOT-AG-20-008.